Development of Aggressive Pancreatic Ductal Adenocarcinomas Depends on Granulocyte Colony Stimulating Factor Secretion in Carcinoma Cells

摘要: The survival rate for pancreatic ductal adenocarcinoma (PDAC) remains low. More therapeutic options to treat this disease are needed, the current standard of care is ineffective. Using an animal model aggressive PDAC (Kras/p48TGFβRIIKO), we discovered effect TGFβ signaling in regulation G-CSF secretion epithelium. Elevated concentrations promoted differentiation Ly6G+ cells from progenitors, stimulated IL10 myeloid cells, and decreased T-cell proliferation via upregulation Arg, iNOS, VEGF, IL6, IL1b CD11b+ cells. Deletion csf3 or use a G-CSF-blocking antibody tumor growth. Anti-G-CSF treatment combination with DNA synthesis inhibitor gemcitabine reduced size, increased number infiltrating T more effectively than alone. Human analysis human datasets Cancer Genome Atlas tissue microarrays correlated observations our mouse experiments, especially patients grade 1, stage II disease. We propose that PDAC, elevated contributes progression through promoting increases infiltration neutrophil-like high immunosuppressive activity. Such mechanism provides avenue neoadjuvant approach devastating Immunol Res; 5(9); 718-29. ©2017 AACR.